Craniosynostosis is a common birth defect that affects newborns at a frequency of approximately 1 in 3000. The hallmark of this disorder is an abnormal fusion of the cranial sutures, resulting in severe dysmorphosis. In humans, mutations in FGF receptors and in the MSX2 gene are responsible for a subset of craniosynostoses. The applicant proposes that various signal transduction systems interact to regulate morphogenesis during development and articulates the goal of integrating components of the coordinated regulatory system participating in normal development of the skull and cranial sutures. Instead of focusing on the relationship between FGFs and Msx2, however, the applicant will investigate the regulatory role of the Bone Morphogenetic Protein (BMP) signaling pathway in the morphogenesis of calvarial bones and sutures, and he will test genetic interactions between Smadl, a signal transduction component of BMP signaling and Msx1 and Msx2. Smadl, a vertebrate homologue of Drosophila, Mad gene, is a direct target for the BMP type I receptor serine-threonine kinase. Upon BMP binding to the receptor, the receptor phosphorylates Smadl which translocates to the nucleus and cooperates with other Smads and transcriptional regulatory proteins to activate downstream genes. The expression of Smadl during mouse embryogenesis and calvarial suture formation has not been previously described. Msx1 and 2 represent additional candidate molecules for the signaling cascade involved in suture morphogenesis. The MSX2 gene is mutated in the human autosomal dominant genetic disorder Boston type craniosynostosis, and during his postdoctoral work, the applicant has shown that transgenic mice overexpressing Msx2 under either homologous or heterologous promoters exhibit premature closure of the calvarial sutures as a consequence of excessive bone growth. The applicant has also observed a similar phenotype affecting calvarial sutures when Msx1 is overexpressed. In addition, ectopic application of BMP in the skull can induce formation of extra bone, and it is known that in other contexts exogenous BMP can modulate Msx expression. These results tie the BMP and Msx genes together in a common developmental process. The applicant proposes that Smad acts to modulate Msx activities and that the identification of such a regulatory interaction would provide fundamental information about the structure of the regulatory network, about the development and maintenance of the cranial sutures and, in the long term, about other genes that are involved in this regulatory network.